Non-coding genetic variants dominant in African American reveal prostate cancer risk

Prostate cancer (PrCa) manifests substantial variation in incidence rates among distinct populations. African American (AA) men are more likely to be diagnosed with and die from PrCa than European American (EA) men. Despite ongoing advancements in identifying polygenic risk variants from large genome-wide association study (GWAS) cohorts, the genetic mechanisms underlying the higher prevalence of PrCa in AA men remain unclear. A systematic approach that does not rely on extensive cohorts to identify causal regulatory variants contributing to PrCa development is still lacking. Here, by employing a sequence-based deep learning model of prostate regulatory enhancers, we identified ~2,000 essential SNPs (eSNPs) with increased alternative allele frequency in AA and which potentially affect the enhancer function leading to greater PrCa susceptibility. The identified eSNPs potentially mediate PrCa development through two complementary mechanisms: alternative alleles with increased enhancer activity are associated with immune system suppression, while those with decreased enhancer activity are linked to differentiation processes. Interestingly, the eSNPs disrupt the binding of key prostate transcription factors including FOX, AR and HOX families, collectively contributing to PrCa predisposition. Together these eSNPs can be used to assess polygenic risk score that is more effective than previous GWAS-based risk scores in distinguishing individuals with PrCa from the control.